Crescentic glomerulonephritis associated with vascular endothelial growth factor (VEGF) inhibitor and bisphosphonate administration

Stylianou, Kostas; Lioudaki, Eirini; Papadimitraki, E.; Kokologiannakis, George; Kroustalakis, Nikos; Liotsi, Christina; Giannakakis, Konstantinos; Georgoulias, V.; Daphnis, Eugenios

doi:10.1093/ndt/gfr093

Cited by 21 publications

(9 citation statements)

References 14 publications

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“…Agents targeting VEGF and/or its receptors (eg, bevacizumab, a humanized anti-VEGF monoclonal antibody, as well as inhibitors that target several receptor tyrosine kinases, including VEGF receptors) have been shown in several preclinical and clinical studies to be associated with increased risks of hypertension and proteinuria from endotheliosis and thrombotic microangiopathy. 208,212–216 Consistent with these data, deletion and knockdown of podocytespecific VEGF-A in mice have resulted in thrombotic microangiopathy, glomerular endotheliosis, proteinuria, and podocyte effacement. 208,210,217,218 …”

Section: Hemodynamic Pathways and Vegfsupporting

confidence: 58%

New Insights Into Molecular Mechanisms of Diabetic Kidney Disease

Badal

Danesh

2014

American Journal of Kidney Diseases

159

107

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Diabetic kidney disease remains a major microvascular complication of diabetes and the most common cause of chronic kidney failure requiring dialysis in the United States. Medical advances over the past century have substantially improved the management of diabetes mellitus and thereby have increased patient survival. However, current standards of care reduce but do not eliminate the risk of diabetic kidney disease, and further studies are warranted to define new strategies for reducing the risk of diabetic kidney disease. In this review, we highlight some of the novel and established molecular mechanisms that contribute to the development of the disease and its outcomes. In particular, we discuss recent advances in our understanding of the molecular mechanisms implicated in the pathogenesis and progression of diabetic kidney disease, with special emphasis on the mitochondrial oxidative stress and microRNA targets. Additionally, candidate genes associated with susceptibility to diabetic kidney disease and alterations in various cytokines, chemokines, and growth factors are addressed briefly.

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Section: Hemodynamic Pathways and Vegfsupporting

confidence: 58%

New Insights Into Molecular Mechanisms of Diabetic Kidney Disease

Badal

Danesh

2014

American Journal of Kidney Diseases

159

107

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“…VEGFi-induced proteinuria might result from acute hypertension [8], and also from direct effects of VEGF antagonism on the glomerulus. VEGF is an important determinant of normal glomerular function [26], and experimental models show that blocking renal VEGF results in down-regulation of tight junction proteins such as nephrin, with consequent proteinuria [21], [27], [28].…”

Section: Discussionmentioning

confidence: 99%

Systematic Review of the Risk of Adverse Outcomes Associated with Vascular Endothelial Growth Factor Inhibitors for the Treatment of Cancer

et al. 2014

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BackgroundAnti-angiogenic therapy targeted at vascular endothelial growth factor (VEGF) is now used to treat several types of cancer. We did a systematic review of randomized controlled trials (RCTs) to summarize the adverse effects of vascular endothelial growth factor inhibitors (VEGFi), focusing on those with vascular pathogenesis.Methods and FindingsWe searched MEDLINE, EMBASE and Cochrane Library until April 19, 2012 to identify parallel RCTs comparing a VEGFi with a control among adults with any cancer. We pooled the risk of mortality, vascular events (myocardial infarction, stroke, heart failure, and thromboembolism), hypertension and new proteinuria using random-effects models and calculated unadjusted relative risk (RR). We also did meta-regression and assessed publication bias. We retrieved 83 comparisons from 72 studies (n = 38,078) on 11 different VEGFi from 7901 identified citations. The risk of mortality was significantly lower among VEGFi recipients than controls (pooled RR 0.96, 95% confidence interval [CI] 0.94 to 0.98, I2 = 0%, tau2 = 0; risk difference 2%). Compared to controls, VEGFi recipients had significantly higher risk of myocardial infarction (MI) (RR 3.54, 95% CI 1.61 to 7.80, I2 = 0%, tau2 = 0), arterial thrombotic events (RR 1.80, 95% CI 1.24 to 2.59, I2 = 0%, tau2 = 0); hypertension (RR 3.46, 95% CI 2.89 to 4.15, I2 = 58%, tau2 = 0.16), and new proteinuria (RR 2.51, 95% CI 1.60 to 3.94, I2 = 87%, tau2 = 0.65). The absolute risk difference was 0.8% for MI, 1% for arterial thrombotic events, 15% for hypertension and 12% for new proteinuria. Meta-regression did not suggest any statistically significant modifiers of the association between VEGFi treatment and any of the vascular events. Limitations include heterogeneity across the trials.ConclusionsVEGFi increases the risk of MI, hypertension, arterial thromboembolism and proteinuria. The absolute magnitude of the excess risk appears clinically relevant, as the number needed to harm ranges from 7 to 125. These adverse events must be weighed against the lower mortality associated with VEGFi treatment.

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“…The renal pathology diagnoses that have been documented to date in these patients include, cryoglobulinemic glomerulonephritis (GN) [51] in a chronic lymphocytic leukemia patient, acute interstitial nephritis attributed to sunitinib and sorafenib [52, 53], collapsing and crescentic GNs thought to reflect the combined toxicity of an intravenous bisphosphonate and anti-angiogenic treatment [12, 54, 55], and focal segmental glomerulosclerosis plus thrombotic microangiopathy in a patient with mRCC on sunitinib [56]. The most common renal pathologic findings, and also the ones most associated with VEGF derangement, are endotheliosis and thrombotic microangiopathy (TMA), indicative of vascular damage (Figure 2) [2, 27, 57, 58].…”

Section: Renal Pathologymentioning

confidence: 99%

VEGF Inhibition, Hypertension, and Renal Toxicity

et al. 2012

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The use of anti-angiogenic agents as part of the therapeutic armamentarium for advanced stage solid tumors has become standard of care in several instances, particularly for renal cell carcinoma, non-small cell lung carcinoma, colorectal carcinoma, and gastrointestinal stromal tumors. These agents primarily target vascular endothelial growth factor (VEGF) and/or its receptors, and include bevacizumab, a humanized monoclonal antibody against VEGF, as well as tyrosine kinase inhibitors that target several receptor tyrosine kinases (RTK), including VEGF receptors. These therapies, as a general class of angiogenic medications, have been shown to have common adverse vascular effects attributable directly or indirectly to their anti-VEGF effects, including hypertension, renal vascular injury, often manifested by proteinuria and thrombotic microangiopathy, and congestive heart failure. Knowledge of these common side effects and their underlying mechanisms may allow for more accurate and prompt diagnoses, timely clinical interventions, and the development of rational and standard treatments. These measures may minimize patient morbidity and mortality, not only by the treatment of side effects, but also by minimizing the disruption of treatment of the underlying malignancy, as well as improving patient quality of life.

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Crescentic glomerulonephritis associated with vascular endothelial growth factor (VEGF) inhibitor and bisphosphonate administration

Cited by 21 publications

References 14 publications

New Insights Into Molecular Mechanisms of Diabetic Kidney Disease

New Insights Into Molecular Mechanisms of Diabetic Kidney Disease

Systematic Review of the Risk of Adverse Outcomes Associated with Vascular Endothelial Growth Factor Inhibitors for the Treatment of Cancer

VEGF Inhibition, Hypertension, and Renal Toxicity

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